The Yale Core Center for Musculoskeletal Disorders (YCCMD) will unite under a single umbrella the talents and skills of 25 investigators from Yale Medical School, Yale University and the John B. Pierce Laboratory. Development, Bone Cell Biology, Cytokines & Growth Factors, Metabolic Bone Disease and Skeletal Biomechanics. YCCMD investigators, based in multiple departments and divisions, share a common goal of understanding the fundamental mechanisms of musculoskeletal disease through the in vivo and in vitro analysis of animal models. Core facilities have been created to facilitate and support the this approach. The Molecular Core will permit the efficient design and generation of molecular regents for tissue-specific transgene over-expression or targeted gene deletions relevant to musculoskeletal disease. The core will also support molecular analysis such as in situ hybridization. The Physiology Core will support densitometric, histomorphometric and biochemical bone- marker analyses to permit detailed evaluation of skeletal homeostasis in experimental animals. The Cell Core will allow investigators to culture osteoblasts, osteoclast-like cells and prepares osteoclasts from animals for in vitro studies. The first period of Pilot and Feasibility proposals have been evaluated and three chosen to complement each other and to foster collaborative interactions between groups that may not have interacted previously. Submitted principally by promising young investigators, they reflect the depth of our Research Base. The first study will examine the cellular localization of the PEX protein, a novel metalloendopeptidase which is functionally deficient in X-linked dominant hypophosphatemic rickets. The application proposes a transgenic rescue of a murine model for this disease. The third study analyzes the molecular details of calcitonin signaling in osteoclasts which will help further define the biology of this critical cell type. The final study will explore the physiologic differences between the soluble and cell surface forms of CSF-1. The goals of the YCCMD are to foster collaboration between biomedical scientists and investigative clinicians and to support education, training, and scientific innovation directed at our shared goal of improving musculoskeletal health.